Live animals, perfused organs, isolated cells, and artificial membranes are used to explore the physiology of bile formation and hepatic solute transport at a fundamental level. There is a strong emphasis on biophysical techniques, mathematical modeling, and computer simulation to achieve these objectives. The long term goal is to understand the pathogenesis of such human afflictions as cholestasis and cholelithiasis, the effect of these diseases on the normal excretion and metabilism of endogenous products like bilirubin, bile acids, and long chain fatty acids and to elucidate the pharmacokinetics of hepatic drug disposal. More immediate objectives are to devise and validate new ways to measure the rate constants for hepatic transport and to unravel the mystery of how the liver deals efficiently with organic solutes that arrive in the afferent circulation bound to plasma proteins.